Guanidine Derivatives of Quinazoline-2,4(1<i>H</i>,3<i>H</i>)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents
Quinazolines are a rich source of bioactive compounds. Previously, we showed NHE-1 inhibitory, anti-inflammatory, antiplatelet, intraocular pressure lowering, and antiglycating activity for a series of quinazoline-2,4(1<i>H</i>,3<i>H</i>)-diones and quinazoline-4(3<i>H&...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-10-01
|
| Series: | Life |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2075-1729/12/10/1647 |
| _version_ | 1797471929380110336 |
|---|---|
| author | Alexander Spasov Alexander Ozerov Vadim Kosolapov Natalia Gurova Aida Kucheryavenko Ludmila Naumenko Denis Babkov Viktor Sirotenko Alena Taran Alexander Borisov Elena Sokolova Vladlen Klochkov Darya Merezhkina Mikhail Miroshnikov Nadezhda Ovsyankina Alexey Smirnov Yulia Velikorodnaya |
| author_facet | Alexander Spasov Alexander Ozerov Vadim Kosolapov Natalia Gurova Aida Kucheryavenko Ludmila Naumenko Denis Babkov Viktor Sirotenko Alena Taran Alexander Borisov Elena Sokolova Vladlen Klochkov Darya Merezhkina Mikhail Miroshnikov Nadezhda Ovsyankina Alexey Smirnov Yulia Velikorodnaya |
| author_sort | Alexander Spasov |
| collection | DOAJ |
| description | Quinazolines are a rich source of bioactive compounds. Previously, we showed NHE-1 inhibitory, anti-inflammatory, antiplatelet, intraocular pressure lowering, and antiglycating activity for a series of quinazoline-2,4(1<i>H</i>,3<i>H</i>)-diones and quinazoline-4(3<i>H</i>)-one guanidine derivatives. In the present work, novel <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mi>N</mi><mn>1</mn></msup></semantics></math></inline-formula>,<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mi>N</mi><mn>3</mn></msup></semantics></math></inline-formula>-bis-substituted quinazoline-2,4(1<i>H</i>,3<i>H</i>)-dione derivatives bearing two guanidine moieties were synthesized and pharmacologically profiled. The most potent NHE-1 inhibitor <b>3a</b> also possesses antiplatelet and intraocular-pressure-reducing activity. Compound <b>4a</b> inhibits NO synthesis and IL-6 secretion in murine macrophages without immunotoxicity and alleviates neutrophil infiltration, edema, and tissue lesions in a model of LPS-induced acute lung injury. Hence, we considered quinazoline derivative <b>4a</b> as a potential agent for suppression of cytokine-mediated inflammatory response and acute lung injury. |
| first_indexed | 2024-03-09T19:55:56Z |
| format | Article |
| id | doaj.art-6046407ded4c4c97915720eb3c4bddcd |
| institution | Directory Open Access Journal |
| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-09T19:55:56Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Life |
| spelling | doaj.art-6046407ded4c4c97915720eb3c4bddcd2023-11-24T00:57:51ZengMDPI AGLife2075-17292022-10-011210164710.3390/life12101647Guanidine Derivatives of Quinazoline-2,4(1<i>H</i>,3<i>H</i>)-Dione as NHE-1 Inhibitors and Anti-Inflammatory AgentsAlexander Spasov0Alexander Ozerov1Vadim Kosolapov2Natalia Gurova3Aida Kucheryavenko4Ludmila Naumenko5Denis Babkov6Viktor Sirotenko7Alena Taran8Alexander Borisov9Elena Sokolova10Vladlen Klochkov11Darya Merezhkina12Mikhail Miroshnikov13Nadezhda Ovsyankina14Alexey Smirnov15Yulia Velikorodnaya16Department of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaScientific Center for Innovative Drugs, Volgograd State Medical University, 400087 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaScientific Center for Innovative Drugs, Volgograd State Medical University, 400087 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pharmacology & Bioinformatics, Volgograd State Medical University, 400001 Volgograd, RussiaDepartment of Pathological Anatomy, Volgograd State Medical University, 400131 Volgograd, RussiaDepartment of Pathological Anatomy, Volgograd State Medical University, 400131 Volgograd, RussiaQuinazolines are a rich source of bioactive compounds. Previously, we showed NHE-1 inhibitory, anti-inflammatory, antiplatelet, intraocular pressure lowering, and antiglycating activity for a series of quinazoline-2,4(1<i>H</i>,3<i>H</i>)-diones and quinazoline-4(3<i>H</i>)-one guanidine derivatives. In the present work, novel <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mi>N</mi><mn>1</mn></msup></semantics></math></inline-formula>,<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><msup><mi>N</mi><mn>3</mn></msup></semantics></math></inline-formula>-bis-substituted quinazoline-2,4(1<i>H</i>,3<i>H</i>)-dione derivatives bearing two guanidine moieties were synthesized and pharmacologically profiled. The most potent NHE-1 inhibitor <b>3a</b> also possesses antiplatelet and intraocular-pressure-reducing activity. Compound <b>4a</b> inhibits NO synthesis and IL-6 secretion in murine macrophages without immunotoxicity and alleviates neutrophil infiltration, edema, and tissue lesions in a model of LPS-induced acute lung injury. Hence, we considered quinazoline derivative <b>4a</b> as a potential agent for suppression of cytokine-mediated inflammatory response and acute lung injury.https://www.mdpi.com/2075-1729/12/10/1647NHE-1cytokine releasemacrophagequinazoline-2,4(1<i>H</i>,3<i>H</i>)-dionelung injuryLPS |
| spellingShingle | Alexander Spasov Alexander Ozerov Vadim Kosolapov Natalia Gurova Aida Kucheryavenko Ludmila Naumenko Denis Babkov Viktor Sirotenko Alena Taran Alexander Borisov Elena Sokolova Vladlen Klochkov Darya Merezhkina Mikhail Miroshnikov Nadezhda Ovsyankina Alexey Smirnov Yulia Velikorodnaya Guanidine Derivatives of Quinazoline-2,4(1<i>H</i>,3<i>H</i>)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents Life NHE-1 cytokine release macrophage quinazoline-2,4(1<i>H</i>,3<i>H</i>)-dione lung injury LPS |
| title | Guanidine Derivatives of Quinazoline-2,4(1<i>H</i>,3<i>H</i>)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents |
| title_full | Guanidine Derivatives of Quinazoline-2,4(1<i>H</i>,3<i>H</i>)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents |
| title_fullStr | Guanidine Derivatives of Quinazoline-2,4(1<i>H</i>,3<i>H</i>)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents |
| title_full_unstemmed | Guanidine Derivatives of Quinazoline-2,4(1<i>H</i>,3<i>H</i>)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents |
| title_short | Guanidine Derivatives of Quinazoline-2,4(1<i>H</i>,3<i>H</i>)-Dione as NHE-1 Inhibitors and Anti-Inflammatory Agents |
| title_sort | guanidine derivatives of quinazoline 2 4 1 i h i 3 i h i dione as nhe 1 inhibitors and anti inflammatory agents |
| topic | NHE-1 cytokine release macrophage quinazoline-2,4(1<i>H</i>,3<i>H</i>)-dione lung injury LPS |
| url | https://www.mdpi.com/2075-1729/12/10/1647 |
| work_keys_str_mv | AT alexanderspasov guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT alexanderozerov guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT vadimkosolapov guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT nataliagurova guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT aidakucheryavenko guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT ludmilanaumenko guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT denisbabkov guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT viktorsirotenko guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT alenataran guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT alexanderborisov guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT elenasokolova guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT vladlenklochkov guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT daryamerezhkina guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT mikhailmiroshnikov guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT nadezhdaovsyankina guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT alexeysmirnov guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents AT yuliavelikorodnaya guanidinederivativesofquinazoline241ihi3ihidioneasnhe1inhibitorsandantiinflammatoryagents |